The generation of amyloid beta-protein by proteolytic cleavage of the amyloid precursor protein (APP) is considered to be a central pathogenic event in Alzheimer's disease (AD). However, an exciting recent development is the elucidation of a nuclear signaling pathway that is activated upon Abeta generation by the release of the APP intracellular domain. The overall goal of this proposal is to investigate the biological function of this signaling pathway and its role in Alzheimer's disease. Our preliminary studies demonstrate that APP can signal to the nucleus through a complex with the adaptor protein Fe65 and the transcription factor TIP60, and show that this signaling pathway is stimulated by presenilin/gamma-secretase activity. However, an unexpected finding is that APP can also signal to the nucleus in the absence of presenilin/gamma-secretase activity, suggesting an unanticipated signaling pathway. Moreover, APP signaling is inhibited by familial AD mutations in APP and presenilin-1, and by the pathogenic Abeta42 peptide. Transcriptional profiling experiments show that presenilin/APP signaling regulates an important set of mitochondrial genes, and multiple members of the tetraspanin family that may regulate synapse formation. Furthermore, an inhibitor of presenilin/gamma-secretase activity inhibits synapse formation in cultured hippocampal neurons, which can be restored by the APP intracellular domain. These findings provide the basis for our hypothesis that altered APP signal transduction may contribute to the early stages of AD pathogenesis, including synapse loss and impaired energy metabolism. The studies in this proposal will examine the molecular mechanism of APP signaling using primary neuronal cultures and conditional presenilin-knockout mice. The role of altered APP signaling in the mechanism of Abeta neurotoxicity, and the effects of Abeta aggregation and familial AD mutations will also be investigated. It will be determined if altered APP signaling leads to mitochondrial dysfunction, and to synapse loss through dysregulation of neural tetraspanins. These studies may provide insights into a novel degenerative mechanism involving altered signal transduction, with potentially significant therapeutic implications for Alzheimer's disease.